Plasma high density lipoprotein levels show a strong inverse relationship with atherosclerotic cardiovascular disease. Recently, scavenger receptor B1 (SRB1) has been identified as an authentic functional HDL receptor. SRB1 binds HDL specifically and mediates the selective uptake of HDL cholesteryl esters (CE) by cells. SRB1 is highly expressed in steroidogenic tissues which show greatest selective uptake in vivo. Recent studies show that adrenal SRB1 mRNA is upregulated in apo A-I knock-out and hepatic lipase deficient mice, but not in several other knock-out strains. Since adrenal cholesterol stores are depleted only in the mice deficient in A-I and hepatic lipase, this suggests that SRB1 mediates selective uptake specifically from HDL containing apo A-I, in a process enhanced by HL activity, and that SRB1 expression is under feedback control in response to changes in cellular cholesterol stores. The overall goals of this proposal are to elucidate the mechanisms of selective uptake by SRB1, the role of HDL remodeling by HL and cholesteryl ester transfer protein in this process, the feedback regulation of SRB1 in response to changes in cellular cholesterol pools and the role of SRB1 in lipoprotein metabolism and atherogenesis. The specific aims are 1) to elucidate the molecular determinants of HDL binding and selective lipid uptake by SRB1; 2) to evaluate the possible feedback regulation of SRB1 in response to HDL-mediated changes in cellular cholesterol pools in adrenal and liver; 3) to use SRB1 transgenic and knock-out mice to study the role of SRB1 in selective uptake of HDL lipids, reverse cholesterol transport and atherogenesis; 4) to evaluate the potential role of SRB1 in human HDL metabolism by searching for mutations. One hypothesis that will be investigated is that SRB1 upregulation in the liver results in enhanced reverse cholesterol transport and decreased atherogenesis. The research will provide new information on the role of SRB1 in HDL metabolism and atherogenesis, and will help to define how SRB1 interacts with other components of the reverse cholesterol transport system.